EP0966455B1 - Oxiran carboxylic acids for the treatment of diabetes - Google Patents

Oxiran carboxylic acids for the treatment of diabetes Download PDF

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EP0966455B1
EP0966455B1 EP98909391A EP98909391A EP0966455B1 EP 0966455 B1 EP0966455 B1 EP 0966455B1 EP 98909391 A EP98909391 A EP 98909391A EP 98909391 A EP98909391 A EP 98909391A EP 0966455 B1 EP0966455 B1 EP 0966455B1
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substituted
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lower alkyl
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EP0966455A1 (en
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Horst P.O. Dr. Wolf
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WOLF, HORST P.O., DR.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D303/00—Compounds containing three-membered rings having one oxygen atom as the only ring hetero atom
    • C07D303/02—Compounds containing oxirane rings
    • C07D303/48—Compounds containing oxirane rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms, e.g. ester or nitrile radicals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the invention relates to new arylalkyl- or aryloxyalkyl-substituted oxirane carboxylic acids, Process for their preparation, their application and containing them Drug.
  • EP 0 231 367 B1 describes the use of the compounds of the general Formula A for the prevention and / or treatment of diseases based on a increased cholesterol and / or triglyceride concentration in the organism, described.
  • DE-OS 4 340 879 A1 describes the use of the compounds of the general formula A described in the prevention and / or treatment of heart failure.
  • No. 4,324,796 describes 2-arylalkyl-substituted oxirane-2-carboxylic acid derivatives, the aryl radical having two substituents R 1 and R 2 , and R 1 and R 2 being a hydrogen, halogen, a hydroxyl group, a lower alkyl, lower alkoxy or a trifluoromethyl group can. These compounds are hypoglycemic.
  • No. 4,337,267 describes 2-aryloxyalkyl-substituted oxirane-2-carboxylic acid derivatives, in particular ethyl 2- (6- (4-chlorophenoxy) hexyl) oxirane-2-carboxylate, where the aryl radical has substituents R 1 and R 2 , and R 1 and R 2 can be a hydrogen, halogen, a lower alkyl, lower alkoxy, a nitro or a trifluoromethyl group. These compounds are hypoglycemic.
  • US 4,788,306 describes compounds of the general formula where A can be the group -O-, and R 1 and R 2 can independently be hydrogen, a hydroxyl group, a halogenated or non-halogenated lower alkyl group, a lower alkoxy group, a halogenated lower alkylsulfonyl group, a halogen or a nitro group.
  • WO 83/00334 describes compounds of the general formula wherein R 1 and R 2 can be hydrogen, a halogen atom, a lower alkyl group, a lower alkoxy group or a trifluoromethyl group. The compounds are examined for their suitability for the treatment of diabetes.
  • the 1-4 C-lower alkyl radicals can be straight-chain or branched.
  • straight- Examples of alkyl radicals are the methyl, ethyl, n-propyl and butyl radicals of those with 1 to 2 carbon atoms are preferred.
  • Branched alkyl residues are for example the isopropyl, isobutyl and the sec-butyl radical, of which the 3 carbon atoms is preferred.
  • the Methoxy group is preferred as the lower alkyl group.
  • alkyl residues in acyl groups straight-chain as well as branched lower alkyl groups are possible, from which the methyl group and the tert. Butyl group are preferred.
  • Halogen atoms are fluorine, chlorine and bromine atoms, of which fluorine, in particular Chlorine is preferred.
  • the substituents R 1 and R 2 are preferably in the m or p position and R 1 is preferably a hydrogen atom.
  • 1-3 C-alkoxy groups which are completely or predominantly substituted with fluorine are the trifluoro-methoxy, the 2,2,2-trifluoroethoxy, the 1,1,2,2-tetrafluoroethoxy group and particularly preferred the difluoromethoxy group.
  • Suitable salts are salts with inorganic and organic bases. Salts which are pharmacologically incompatible are prepared by methods known per se in pharmacological, i.e. biologically compatible salts transferred among the inventive Salts are preferred. As cations for salt formation are before all the cations of the alkali metals, alkaline earth metals or precious metals used, however, the corresponding cations of organic nitrogen bases also come such as amines, amino alcohols, amino sugars, basic amino acids etc. for use.
  • the arylalkyl or aryloxyalkyloxirane carboxylic acids of the general Formula I have a chirality center.
  • the invention therefore includes both the racemates and the enantiomers as well as their mixtures.
  • the carboxylic acids are salts with optically active bases such as cinchonidine or dehydroabietylamine is particularly preferred.
  • the compounds according to the invention have valuable pharmacological properties that make them commercially usable. They are hypoglycemic and lipid-lowering and improve the effectiveness of insulin in the treatment of insulin resistant conditions such as in the metabolic syndrome and in particular for type 2 diabetes.
  • inventive Compounds of the general formula I and the pharmacologically acceptable ones Salts for human and veterinary treatment and prophylaxis diseases based on disorders of glucose and fat metabolism, suitable.
  • they are used to treat prediabetic conditions; to Treatment and prevention of the manifestation of type 2 diabetes and all pathological conditions that are associated with pathological insulin resistance; to treat and prevent the manifestation of all pathological conditions with pathologically increased ketone body production; for treatment and prevention the manifestation of all pathological conditions related to increased cholesterol and / or Triglyceride concentrations in the blood are based (hyperlipidemia, arteriosclerosis, coronary heart desease).
  • the invention also relates to the compounds according to the invention for use in the treatment and prophylaxis of the specified diseases.
  • the invention also relates to the use of the invention Compounds for the manufacture of medicaments for combating the specified Diseases.
  • the pharmaceuticals are manufactured according to methods known per se.
  • the compounds according to the invention are used as medicaments either as such or, if appropriate, in combination with suitable pharmaceutical carriers. If the pharmaceutical preparations contain pharmaceutical carriers in addition to the active ingredients, the active ingredient content of this mixture is 1 to 95%, preferably 10 to 85% (w / w) of the total mixture.
  • the drugs are formulated, for example, for oral or parenteral (intravenous, intramuscular) administration in suitable doses.
  • the daily dose for oral administration to humans is generally between 0.1 and 30, preferably 0.3 and 15, in particular 0.6 and 3 mg / kg body weight.
  • the dosage for parenteral treatment is between 0.3 and 1 mg of active ingredient / kg body weight.
  • the pharmaceutical preparations preferably consist of the active substances according to the invention and non-toxic, pharmaceutically acceptable medicament carriers, which are added as an admixture or diluent in solid, semi-solid, or liquid form or as enveloping agents, for example in the form of a capsule, a tablet cover, a sachet or another container for the therapeutically active ingredient.
  • a carrier can serve, for example, as a mediator for the absorption of pharmaceuticals by the body, as a formulation aid, as a sweetener, as a taste corrector, as a color or as a preservative.
  • the pharmaceutical preparations furthermore one or more pharmacologically active ingredients in other groups of drugs, such as antidiabetic drugs (sulfonamides, Sulfonylureas, thiazolidinediones, etc.) or hypolipidemics (nicotinic acid and their derivatives, clofibrates, HMG-CoA reductase inhibitors) contain.
  • antidiabetic drugs sulfonamides, Sulfonylureas, thiazolidinediones, etc.
  • hypolipidemics nicotinic acid and their derivatives, clofibrates, HMG-CoA reductase inhibitors
  • the compounds according to the invention are prepared by processes known per se. Detailed instructions for the production of the basic class of compound are described in the aforementioned EP 0046 590, which is included in the disclosure of this application with regard to process engineering. These regulations can be applied in analogy process steps to the new compounds according to the invention.
  • the person skilled in the art can readily introduce the novel meanings according to the invention for the radical R 2 compared to the European application mentioned, which are customary chemically per se, using numerous standard methods.
  • the compounds of general formula I usually fall in the form of racemic mixtures in the enantiomers by known methods be separated. For example, one uses an optically active cleavage agent the racemate into diastereomers, which are then converted by selective crystallization separated and converted into the corresponding optical isomers.
  • optically active splitting agents e.g. optically active bases, such as 1- and d-1-phenylethylamine, Cinchonidine or d-ephedrine, from which salts of the acids of the general Formula I, or optically active alcohols, such as borneol or menthol, with which esters are prepared from the acids of general formula I.
  • optically active bases such as 1- and d-1-phenylethylamine, Cinchonidine or d-ephedrine
  • optically active alcohols such as borneol or menthol
  • esters are prepared from the acids of general formula I.
  • the resolution of the racemates by means of dehydroabiethylamine has been suitable exposed
  • the compounds of the formula I according to the invention lower the glucose concentration in the blood of rats that have been fasting into an insulin resistant Condition. With this effect they show up from the Active substances known in the art, e.g. rac-etomoxir (see EP 046 590) think.
  • connection 1 (6- (4-chlorophenoxy) hexyl) oxirane-2-carboxylic acid ethyl ester (comparative compound) 2 2- (6- (4-Difluormethoxyphenoxy) hexyl) oxirane-2-carboxylic acid ethyl ester 3 2- (5- (4-Difluormethoxyphenoxy) pentyl) oxirane-2-carboxylic acid ethyl ester 4 2- (5- (4-acetylphenoxy) pentyl) oxirane-2-carboxylate
  • the insulin resistance model is particularly evident in the example of substances Nos. 2 and 3 in Tab. 1. Taking into account the triglyceride and cholesterol-lowering Effect No. 3 is particularly characterized by the state of the art Technology superior effect.
  • substance no. 4 stands out as the state of the art superior.
  • Substances Nos. 2 and 3 are also state of the art think.
  • mice Male Sprague-Dawley rats from SPF-Zuchr Ivanovas (Kisslegg, Germany) with a body mass of 255-400 g were used as test animals. The animals were kept conventionally with 4 animals each in Mkrolon cages (22 x 38 cm) in a temperature-controlled room (21-23 degrees Celsius) with a fixed day / night rhythm (7/7 p.m.) and regulated relative humidity of 55 - 60%. The animals were offered an Altromin 1320 husbandry diet from Altromin (Lage, Germany) and water ad libitum.
  • the animals were randomly divided into 5 groups of 10 animals each and marked.
  • the substances were administered to the animals in the form of a neutral, aqueous emulsion (1st Part by weight of substance + 2 parts by weight of Cremophor EL - an emulsifier from BASF AG, Germany -) using a gastric tube in a volume of 10 ml / kg Body weight administered.
  • the 24-day fasting animals were Hours after substance administration, 50 ⁇ l of blood was drawn out using a Gals capillary taken from the retrobulbar venous plexus and in ice-cold perchloric acid (0.66 mol / l) deproteinized. After centrifugation, the glucose was determined in the Supernatant according to standard enzymatic methods.

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  • Health & Medical Sciences (AREA)
  • Diabetes (AREA)
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Abstract

The invention relates to novel arylalkyl- or aryloxyalkyl-substituted oxiranecarboxylic acids of the general formula I:in which Ar, R<3>, Y and n are as defined in the description, and also to medicaments comprising them and to their use for the treatment and prophylaxis of the disorders mentioned in claim 4 which are caused by disturbances of glucose and/or lipid metabolism, such as, for example, diabetes type 2 and other insulin-resistant conditions.

Description

Anwendungsgebiet der ErfindungField of application of the invention

Die Erfindung betrifft neue Arylalkyl- bzw. Aryloxyalkyl-substituierte Oxirancarbonsäuren, Verfähren zu ihrer Herstellung, ihre Anwendung und sie enthaltende Arzneimittel.The invention relates to new arylalkyl- or aryloxyalkyl-substituted oxirane carboxylic acids, Process for their preparation, their application and containing them Drug.

Stand der TechnikState of the art

In der EP 0 046 590 werden hypoglykämisch und hypoketonämisch wirksame Phen(alk)oxy-substituierte Oxirancarbonsäuren und deren Ester der allgemeinen Formel A beschrieben

Figure 00010001
worin

R1
ein Wasserstoffatom, ein Halogenatom, eine 1-4 C-Niederalkylgruppe, eine 1-4 C-Niederalkoxygruppe, eine Nitrogruppe oder eine Trifluormethylgruppe bedeutet,
R2
eine Bedeutung von R1 hat,
R3
ein Wasserstoffatom oder eine 1-4 C-Niederalkylgruppe,
Y
die Gruppierung -O-(CH2)m -,
m
0 oder eine ganze Zahl von 1 bis 4 und
n
eine ganze Zahl von 1 bis 8 bedeuten,
wobei die Summe von m und n eine ganze Zahl von 2 bis 8 ist, sowie die Salze der Carbonsäuren. EP 0 046 590 describes phen (alk) oxy-substituted oxirane carboxylic acids and their esters of the general formula A which are hypoglycemic and hypoketonemic
Figure 00010001
wherein
R 1
represents a hydrogen atom, a halogen atom, a 1-4 C-lower alkyl group, a 1-4 C-lower alkoxy group, a nitro group or a trifluoromethyl group,
R 2
has a meaning of R1,
R 3
a hydrogen atom or a 1-4 C-lower alkyl group,
Y
the grouping -O- (CH 2 ) m -,
m
0 or an integer from 1 to 4 and
n
is an integer from 1 to 8,
where the sum of m and n is an integer from 2 to 8, and the salts of the carboxylic acids.

In der EP 0 231 367 B1 ist die Verwendung der Verbindungen der allgemeinen Formel A für die Verhütung und/oder Behandlung von Krankheiten, die auf einer erhöhten Cholesterin- und/oder Triglycerid-Konzentration im Organismus beruhen, beschrieben.EP 0 231 367 B1 describes the use of the compounds of the general Formula A for the prevention and / or treatment of diseases based on a increased cholesterol and / or triglyceride concentration in the organism, described.

In der DE-OS 4 340 879 A1 ist der Einsatz der Verbindungen der allgemeinen Formel A bei der Verhütung und/oder Behandlung der Herzinsuffizienz beschrieben.DE-OS 4 340 879 A1 describes the use of the compounds of the general formula A described in the prevention and / or treatment of heart failure.

In der DE-OS 3 032 668 werden u.a. nicht-aromatische Cycloalkyl(alk)oxysubstituierte Oxirancarbonsäuren beschrieben.In DE-OS 3 032 668 i.a. non-aromatic cycloalkyl (alk) oxy-substituted Oxirane carboxylic acids described.

In der EP 0 283 168 werden Phenylalkyl- und Phenoxyalkyloxirancarbonsäuren und deren Ester mit 1-2 Fluorsubstituenten in der Alkylkette beschrieben, die als Fettsäureoxidationsinhibitoren mit geringem Schädigungspotential für die Herzmuskelfunktion wirken sollen.In EP 0 283 168 phenylalkyl and phenoxyalkyloxirane carboxylic acids and whose esters are described with 1-2 fluorine substituents in the alkyl chain, which act as fatty acid oxidation inhibitors with little damage potential for the heart muscle function should work.

US 4,324,796 beschreibt 2-Arylalkyl-substituierte Oxiran-2-carbonsäurederivate, wobei der Arylrest zwei Substituenten R1 und R2 aufweist, und R1 und R2 ein Wasserstoff, Halogen, eine Hydroxylgruppe, eine Niederalkyl-, Niederalkoxy- oder eine Trifluormethylgruppe sein kann. Diese Verbindungen weisen hypoglykämische Wirkung auf.No. 4,324,796 describes 2-arylalkyl-substituted oxirane-2-carboxylic acid derivatives, the aryl radical having two substituents R 1 and R 2 , and R 1 and R 2 being a hydrogen, halogen, a hydroxyl group, a lower alkyl, lower alkoxy or a trifluoromethyl group can. These compounds are hypoglycemic.

US 4,337,267 beschreibt 2-Aryloxyalkyl-substituierte Oxiran-2-carbonsäurederivate, insbesondere 2-(6-(4-Chlorphenoxy)hexyl)oxiran-2-carbonsäureethylester, wobei der Arylrest Substituenten R1 und R2 aufweist, und R1 und R2 ein Wasserstoff, Halogen, eine Niederalkyl-, Niederalkoxy-, eine Nitro- oder eine Trifluormethylgruppe sein kann. Diese Verbindungen weisen hypoglykämische Wirkung auf.No. 4,337,267 describes 2-aryloxyalkyl-substituted oxirane-2-carboxylic acid derivatives, in particular ethyl 2- (6- (4-chlorophenoxy) hexyl) oxirane-2-carboxylate, where the aryl radical has substituents R 1 and R 2 , and R 1 and R 2 can be a hydrogen, halogen, a lower alkyl, lower alkoxy, a nitro or a trifluoromethyl group. These compounds are hypoglycemic.

US 4,788,306 beschreibt Verbindungen der allgemeinen Formel

Figure 00020001
wobei A die Gruppe -O- sein kann, sowie R1 und R2 unabhängig voneinander Wasserstoff, eine Hydroxylgruppe, eine halogenierte oder nicht-halogenierte Niederalkylgruppe, eine Niederalkoxygruppe, eine halogenierte Niederalkylsulfonylgruppe, ein Halogen oder eine Nitrogruppe sein können. X ist ausgewählt aus der Gruppe bestehend aus -CH2-CH(F)-, -CH2-CF2- oder -CH=CF-. Diese Verbindungen werden bezüglich ihrer Eignung zur Behandlung von Diabetes untersucht.US 4,788,306 describes compounds of the general formula
Figure 00020001
where A can be the group -O-, and R 1 and R 2 can independently be hydrogen, a hydroxyl group, a halogenated or non-halogenated lower alkyl group, a lower alkoxy group, a halogenated lower alkylsulfonyl group, a halogen or a nitro group. X is selected from the group consisting of -CH 2 -CH (F) -, -CH 2 -CF 2 - or -CH = CF-. These compounds are being investigated for their suitability for the treatment of diabetes.

WO 83/00334 beschreibt Verbindungen der allgemeinen Formel

Figure 00020002
wobei R1 und R2 Wasserstoff, ein Halogenatom, eine Niederalkylgruppe, eine Niederalkoxygruppe oder eine Trifluormethylgruppe sein kann. Die Verbindungen werden bezüglich ihrer Eignung zur Behandlung von Diabetes untersucht.WO 83/00334 describes compounds of the general formula
Figure 00020002
wherein R 1 and R 2 can be hydrogen, a halogen atom, a lower alkyl group, a lower alkoxy group or a trifluoromethyl group. The compounds are examined for their suitability for the treatment of diabetes.

Beschreibung der ErfindungDescription of the invention

Gegenstand der Erfindung sind neue Arylalkyl- bzw. Aryloxyalkyl-substituierte Oxirancarbonsäuren der allgemeinen Formel I

Figure 00020003
worin

Ar
einen substituierten Phenylrest
Figure 00020004
einen mit einem Rest R4 substituierten 1- oder 2-Naphthylrest oder einen heterocyclischen Rest Het,
R1
ein Wasserstoffatom, ein Halogenatom oder eine 1-4 C-Niederalkylgruppe,
R2
eine der Gruppen
Figure 00040001
oder eine vollständig oder überwiegend mit Fluor substituierte 1-3 C-Alkoxygruppe,
R3
ein Wasserstoffatom oder eine 1-4 C-Niederalkylgruppe,
R4
ein Wasserstoffatom, eine 1-4 C-Niederalkylgruppe, eine gegebenfalls vollständig oder überwiegend mit Fluor substituierte 1-3 C-Alkoxygruppe oder ein Halogenatom,
R5
eine 1-4 C-Niederalkylgruppe,
Y
die Gruppierung - O - ,
n
eine ganze Zahl von 2-8 und
Het
einen heterocyclischen Ring mit 5 Gliedern und aus der Gruppe Thiophen, Thiazol, Isothiazol, Pyrrol und besonders bevorzugt Pyrazol, welcher 1-2 gleiche oder verschiedene Substituenten R' tragen kann,
bedeuten, wobei die Kette - (CH2)n - gegebenfalls auch durch ein Glied - CH(CH3) - oder - C(CH3)2 - unterbrochen sein kann, sowie die Salze der entsprechenden Carbonsäuren (R3 = H).The invention relates to new arylalkyl- or aryloxyalkyl-substituted oxirane carboxylic acids of the general formula I.
Figure 00020003
wherein
Ar
a substituted phenyl radical
Figure 00020004
a 1- or 2-naphthyl radical substituted by a radical R 4 or a heterocyclic radical Het,
R 1
a hydrogen atom, a halogen atom or a 1-4 C-lower alkyl group,
R 2
one of the groups
Figure 00040001
or a 1-3 C alkoxy group which is completely or predominantly substituted by fluorine,
R 3
a hydrogen atom or a 1-4 C-lower alkyl group,
R 4
a hydrogen atom, a 1-4 C-lower alkyl group, a 1-3 C-alkoxy group which is optionally completely or predominantly substituted with fluorine or a halogen atom,
R 5
a 1-4 C-lower alkyl group,
Y
the grouping - O -,
n
an integer from 2-8 and
Het
a heterocyclic ring with 5 members and from the group thiophene, thiazole, isothiazole, pyrrole and particularly preferably pyrazole, which can carry 1-2 identical or different substituents R ',
mean, where the chain - (CH 2 ) n - may also be interrupted by a link - CH (CH 3 ) - or - C (CH 3 ) 2 -, and the salts of the corresponding carboxylic acids (R 3 = H).

Die 1-4 C-Niederalkylreste können geradkettig oder verzweigt sein. Geradkettige Alkylreste sind beispielsweise der Methyl-, Ethyl-, n-Propyl- und der Butylrest, von denen die mit 1 bis 2 Kohlenstoffatomen bevorzugt sind. Verzweigte Alkylreste sind beispielsweise der Isopropyl-, Isobutyl und der sek.-Butylrest, von denen der mit 3 Kohlenstoffatomen bevorzugt ist. Als Alkylreste von Niederalkoxygruppen kommen sowohl geradkettige als auch verzweigte Niederalkylgruppen in Frage. Die Methoxy-gruppe ist als Niederalkylgruppe bevorzugt. Als Alkylreste in Acylgruppen kommen sowohl geradkettige als auch verzweigte Niederalkylgruppen in Frage, von denen die Methylgruppe und die tert. Butylgruppe bevorzugt sind.The 1-4 C-lower alkyl radicals can be straight-chain or branched. straight- Examples of alkyl radicals are the methyl, ethyl, n-propyl and butyl radicals of those with 1 to 2 carbon atoms are preferred. Branched alkyl residues are for example the isopropyl, isobutyl and the sec-butyl radical, of which the 3 carbon atoms is preferred. Come as alkyl residues of lower alkoxy groups both straight-chain and branched lower alkyl groups in question. The Methoxy group is preferred as the lower alkyl group. As alkyl residues in acyl groups straight-chain as well as branched lower alkyl groups are possible, from which the methyl group and the tert. Butyl group are preferred.

Halogenatome sind Fluor-, Chlor- und Bromatome, von denen Fluor, insbesondere Chlor bevorzugt ist.Halogen atoms are fluorine, chlorine and bromine atoms, of which fluorine, in particular Chlorine is preferred.

In den substituierten Phenylresten Ar stehen die Substituenten R1 und R2 bevorzugt in m- oder p-Stellung und R1 ist bevorzugt ein Wasserstoffatom.In the substituted phenyl radicals Ar, the substituents R 1 and R 2 are preferably in the m or p position and R 1 is preferably a hydrogen atom.

Von den vollständig oder überwiegend mit Fluor substituierten 1-3 C-Alkoxygruppen sind die Trifluor-methoxy-, die 2,2,2-Trifluorethoxy-, die 1,1,2,2-Tetrafluorethoxygruppe und insbesondere die Difluormethoxygruppe bevorzugt.Of the 1-3 C-alkoxy groups which are completely or predominantly substituted with fluorine are the trifluoro-methoxy, the 2,2,2-trifluoroethoxy, the 1,1,2,2-tetrafluoroethoxy group and particularly preferred the difluoromethoxy group.

Als Salze kommen Salze mit anorganischen und organischen Basen in Betracht. Pharmakologisch nicht verträgliche Salze werden nach an sich bekannten Methoden in pharmakologisch, d.h. biologisch verträgliche Salze überführt, die unter den erfindungsgemäßen Salzen bevorzugt sind. Als Kationen für die Salzbildung werden vor allem die Kationen der Alkalimetalle, Erdalkalimetalle oder Edelmetalle verwendet, es kommen jedoch auch die entsprechenden Kationen organischer Stickstoffbasen, wie Amine, Aminoalkohole, Aminozucker, basische Aminosäuren etc. zur Anwendung.Suitable salts are salts with inorganic and organic bases. Salts which are pharmacologically incompatible are prepared by methods known per se in pharmacological, i.e. biologically compatible salts transferred among the inventive Salts are preferred. As cations for salt formation are before all the cations of the alkali metals, alkaline earth metals or precious metals used, however, the corresponding cations of organic nitrogen bases also come such as amines, amino alcohols, amino sugars, basic amino acids etc. for use.

Beispielsweise seien Salze von Lithium, Natrium, Kalium, Magnesium, Calcium, Aluminium, Ethylendiamin, Dimethylamin, Diethylamin, Morpholin, Piperidin, Piperazin, N-Niederalkylpiperazin (z.B. N-Methylpiperazin), Methylcyclohexylamin, Benzylamin, Ethanolamin, Diethanolamin, Triethanolamin, Tris-(hydroxymethyl)-aminomethan, 2-Amino-2-methylpropanol, 2-Amino-2-methyl-1,3-propandiol, Glucamin, N-Methyl-glucamin, Glucosamin, N-Methylglucosamin, Lysin, Ornithin, Arginin, Chinolin genannt. For example, salts of lithium, sodium, potassium, magnesium, calcium, Aluminum, ethylenediamine, dimethylamine, diethylamine, morpholine, piperidine, piperazine, N-lower alkylpiperazine (e.g. N-methylpiperazine), methylcyclohexylamine, Benzylamine, ethanolamine, diethanolamine, triethanolamine, tris (hydroxymethyl) aminomethane, 2-amino-2-methylpropanol, 2-amino-2-methyl-1,3-propanediol, Glucamine, N-methyl-glucamine, glucosamine, N-methylglucosamine, lysine, ornithine, Arginine, called quinoline.

Die erfindungsgemäßen Arylalkyl- bzw. Aryloxyalkyloxirancarbonsäuren der allgemeinen Formel I besitzen ein Chiralitätszentrum. Die Erfindung schließt daher sowohl die Racemate und die Enantiomeren als auch deren Gemische ein. Für die Racemattrennung der Carbonsäuren sind Salze mit optisch aktiven Basen wie Cinchonidin oder Dehydroabietylamin besonders bevorzugt.The arylalkyl or aryloxyalkyloxirane carboxylic acids of the general Formula I have a chirality center. The invention therefore includes both the racemates and the enantiomers as well as their mixtures. For racemate separation The carboxylic acids are salts with optically active bases such as cinchonidine or dehydroabietylamine is particularly preferred.

Die erfindungsgemäßen Verbindungen weisen wertvolle pharmakologische Eigenschaften auf, die sie gewerblich verwertbar machen. Sie wirken hypoglycämisch und lipidsenkend und verbessern die Wirksamkeit von Insulin bei der Behandlung von insulinresistenten Zuständen, wie z.B. beim Metabolischen Syndrom und insbesondere beim Diabetes Typ 2.The compounds according to the invention have valuable pharmacological properties that make them commercially usable. They are hypoglycemic and lipid-lowering and improve the effectiveness of insulin in the treatment of insulin resistant conditions such as in the metabolic syndrome and in particular for type 2 diabetes.

Sie sind den bekannten Oxirancarbonsäuren des Standes der Technik in folgender Weise überlegen:

  • a) Sie zeichnen sich durch einen unter bestimmten Bedingungen deutlich besseren
    therapeutischen Index in der Weise aus, daß die bei einzelnen Typ 2-Diabetikern auftretenden Anstiege der Leberenzyme (Transaminasen) gar nicht oder in deutlich geringerem Ausmaß auftreten,
  • b) sie zeigen eine überlegene Wirkung hinsichtlich der Steigerung der Insulinwirkung bei insulinresistenten Zuständen
  • c) sie werden schneller metabolisiert und bilden keine langlebigen Metaboliten.
    • They are superior to the known oxirane carboxylic acids of the prior art in the following way:
  • a) They are markedly better under certain conditions
    therapeutic index in such a way that the increases in liver enzymes (transaminases) occurring in individual type 2 diabetics do not occur at all or occur to a significantly lesser extent,
  • b) they show a superior effect in increasing the insulin effect in insulin resistant conditions
  • c) they are metabolized faster and do not form long-lived metabolites.

    • Aufgrund ihrer vorteilhaften und überlegenen Wirksamkeit sind die erfindungsgemäßen Verbindungen der allgemeinen Formel I sowie die pharmakologisch verträglichen Salze zur human- und veterinärmedizinischen Behandlung und Prophylaxe von Krankheiten, die auf Störungen des Glucose- und Fettstoffwechsels beruhen, geeignet. Because of their advantageous and superior effectiveness, the inventive Compounds of the general formula I and the pharmacologically acceptable ones Salts for human and veterinary treatment and prophylaxis diseases based on disorders of glucose and fat metabolism, suitable.

    Beispielsweise werden sie eingesetzt zur Behandlung prädiabetischer Zustände; zur Behandlung und Verhinderung der Manifestation des Diabetes Typ 2 sowie aller krankhaften Zustände, die mit einer pathologischen Insulinresistenz einhergehen; zur Behandlung und Verhinderung der Manifestation aller krankhaften Zustände mit pathologisch erhöhter Ketonkörperproduktion; zur Behandlung und Verhinderung der Manifestation aller krankhaften Zustände, die auf erhöhten Cholesterinund/oder Triglycerid-Konzentrationen im Blut beruhen (Hyperlipidämie, Arteriosklerose, koronare Herzerkrankung).For example, they are used to treat prediabetic conditions; to Treatment and prevention of the manifestation of type 2 diabetes and all pathological conditions that are associated with pathological insulin resistance; to treat and prevent the manifestation of all pathological conditions with pathologically increased ketone body production; for treatment and prevention the manifestation of all pathological conditions related to increased cholesterol and / or Triglyceride concentrations in the blood are based (hyperlipidemia, arteriosclerosis, coronary heart desease).

    Gegenstand der Erfindung sind auch die erfindungsgemäßen Verbindungen zur Anwendung bei der Behandlung und Prophylaxe der angegebenen Krankheiten.The invention also relates to the compounds according to the invention for use in the treatment and prophylaxis of the specified diseases.

    Ein weiterer Gegenstand der Erfindung sind Arzneimittel, die eine oder mehrere der Arylalkyl- bzw. Aryloxyalkyloxirancarbonsäuren der allgemeinen Formel I

    Figure 00070001
    worin

    Ar
    einen substituierten Phenylrest
    Figure 00070002
    einen mit einem Rest R4 substituierten 1- oder 2-Naphthylrest oder einen heterocyclischen Rest Het,
    R1
    ein Wasserstoffatom, ein Halogenatom oder eine 1-4 C-Niederalkylgruppe,
    R2
    eine der Gruppen
    Figure 00080001
    oder eine vollständig oder überwiegend mit Fluor substituierte 1-3 C-Alkoxygruppe,
    R3
    ein Wasserstoffatom oder eine 1-4 C-Niederalkylgruppe,
    R4
    ein Wasserstoffatom, eine 1-4 C-Niederalkylgruppe, eine gegebenfalls vollständig oder überwiegend mit Fluor substituierte 1-3 C-Alkoxygruppe oder ein Halogenatom,
    R5
    eine 1-4 C-Niederalkylgruppe,
    Y
    die Gruppierung - O -,
    n
    eine ganze Zahl von 2-8 und
    Het
    einen heterocyclischen Ring mit 5 Gliedern und aus der Gruppe Thiophen, Thiazol, Isothiazol, Pyrrol und besonders bevorzugt Pyrazol, welcher 1-2 gleiche oder verschiedene Substituenten R1 tragen kann,
    bedeuten, wobei die Kette - (CH2)n - gegebenfalls auch durch ein Glied - CH(CH3)-oder - C(CH3)2 - unterbrochen sein kann, sowie die pharmakologisch verträglichen Salze der Carbonsäuren (R3 = H) mit anorganischen oder organischen Basen enthalten.The invention further relates to medicaments which contain one or more of the arylalkyl or aryloxyalkyloxirane carboxylic acids of the general formula I.
    Figure 00070001
    wherein
    Ar
    a substituted phenyl radical
    Figure 00070002
    a 1- or 2-naphthyl radical substituted by a radical R 4 or a heterocyclic radical Het,
    R 1
    a hydrogen atom, a halogen atom or a 1-4 C-lower alkyl group,
    R 2
    one of the groups
    Figure 00080001
    or a 1-3 C alkoxy group which is completely or predominantly substituted by fluorine,
    R 3
    a hydrogen atom or a 1-4 C-lower alkyl group,
    R 4
    a hydrogen atom, a 1-4 C-lower alkyl group, a 1-3 C-alkoxy group which is optionally completely or predominantly substituted with fluorine or a halogen atom,
    R 5
    a 1-4 C-lower alkyl group,
    Y
    the grouping - O -,
    n
    an integer from 2-8 and
    Het
    a heterocyclic ring with 5 members and from the group thiophene, thiazole, isothiazole, pyrrole and particularly preferably pyrazole, which can carry 1-2 identical or different substituents R 1 ,
    mean, where the chain - (CH 2 ) n - may also be interrupted by a link - CH (CH 3 ) or - C (CH 3 ) 2 -, and the pharmacologically acceptable salts of the carboxylic acids (R 3 = H) with inorganic or organic bases.

    Gegenstand der Erfindung ist außerdem die Verwendung der erfindungsgemäßen Verbindungen zur Herstellung von Arzneimitteln zur Bekämpfung der angegebenen Krankheiten.The invention also relates to the use of the invention Compounds for the manufacture of medicaments for combating the specified Diseases.

    Die Arzneimittel werden nach an sich bekannten Verfahren hergestellt. Als Arzneimittel werden die erfindungsgemäßen Verbindungen entweder als solche oder gegebenenfalls in Kombination mit geeigneten pharmazeutischen Trägerstoffen eingesetzt. Enthalten die pharmazeutischen Zubereitungen neben den Wirkstoffen pharmazeutische Trägerstoffe, beträgt der Wirkstoffgehalt dieser Mischung 1 bis 95, vorzugsweise 10 bis 85 % (w/w) der Gesamtmischung. Die Arzneimittel werden beispielsweise für die orale oder parenterale (intravenöse, intramuskuläre) Gabe in geeigneten Dosen formuliert. Die Tagesdosis für die orale Applikation am Menschen liegt im allgemeinen zwischen 0.1 und 30, vorzugsweise 0.3 und 15, insbesondere 0,6 und 3 mg / kg Körpergewicht. Die Dosierung für die parenterale Behandlung liegt zwischen 0.3 und 1 mg Wirkstoff / kg Körpergewicht.
    Die pharmazeutischen Zubereitungen bestehen bevorzugt aus den erfindungsgemäßen Wirkstoffen und nicht-toxischen, pharmazeutisch verträglichen Arzneimittelträgern, die als Zumischung oder Verdünnungsmittel in fester, halbfester, oder flüssiger Form oder als Umhüllungsmittel, beispielsweise in Form einer Kapsel, eines Tablettenüberzugs, eines Beutels oder eines anderen Behältnisses für den therapeutisch aktiven Bestandteil in Anwendung kommen. Ein Trägerstoff kann z.B. als Vermittler für die Arzneimittelaufnahme durch den Körper, als Formulierungshilfsmittel, als Süßungsmittel, als Geschmackskorrigens, als Farbstoff oder als Konservierungsmittel dienen.    The pharmaceuticals are manufactured according to methods known per se. The compounds according to the invention are used as medicaments either as such or, if appropriate, in combination with suitable pharmaceutical carriers. If the pharmaceutical preparations contain pharmaceutical carriers in addition to the active ingredients, the active ingredient content of this mixture is 1 to 95%, preferably 10 to 85% (w / w) of the total mixture. The drugs are formulated, for example, for oral or parenteral (intravenous, intramuscular) administration in suitable doses. The daily dose for oral administration to humans is generally between 0.1 and 30, preferably 0.3 and 15, in particular 0.6 and 3 mg / kg body weight. The dosage for parenteral treatment is between 0.3 and 1 mg of active ingredient / kg body weight.
    The pharmaceutical preparations preferably consist of the active substances according to the invention and non-toxic, pharmaceutically acceptable medicament carriers, which are added as an admixture or diluent in solid, semi-solid, or liquid form or as enveloping agents, for example in the form of a capsule, a tablet cover, a sachet or another container for the therapeutically active ingredient. A carrier can serve, for example, as a mediator for the absorption of pharmaceuticals by the body, as a formulation aid, as a sweetener, as a taste corrector, as a color or as a preservative.

    Neben den erfindungsgemäßen Verbindungen der allgemeinen Formel I, in denen die Substituenten die oben angegebene Bedeutung haben, und/oder ihren Salzen können die pharmazeutischen Zubereitungen weiterhin einen oder mehrere pharmakologisch aktive Bestandteile anderer Arzneimittelgruppen, wie Antidiabetika (Sulfonamide, Sulfonylharnstoffe, Thiazolidindione u.a.) oder Hypolipidämika (Nikotinsäure und deren Derivate, Clofibrate, HMG-CoA-Reduktasehemmer) enthalten.In addition to the compounds of general formula I according to the invention, in which the Substituents have the meaning given above, and / or their salts the pharmaceutical preparations furthermore one or more pharmacologically active ingredients in other groups of drugs, such as antidiabetic drugs (sulfonamides, Sulfonylureas, thiazolidinediones, etc.) or hypolipidemics (nicotinic acid and their derivatives, clofibrates, HMG-CoA reductase inhibitors) contain.

    Die erfindungsgemäßen Verbindungen werden nach an sich bekannten Verfahren hergestellt. Ausführliche Anweisungen für die Herstellung der prinzipiellen Verbindungsklasse sind in der eingangs genannten EP 0046 590 beschrieben, welche in bezug auf die Verfahrenstechnik in die Offenbarung dieser Anmeldung mit eingeschlossen ist. Diese Vorschriften können in Analogieverfahrensschritten auf die neuen erfindungsgemäßen Verbindungen angewendet werden. Die Einführung der neuen erfindungsgemäßen, chemisch aber an sich übliche Bedeutungen für den Rest R2 im Vergleich zu der besagten europäischen Anmeldung kann der Fachmann ohne weiteres nach zahlreichen Standardmethoden bewerkstelligen.The compounds according to the invention are prepared by processes known per se. Detailed instructions for the production of the basic class of compound are described in the aforementioned EP 0046 590, which is included in the disclosure of this application with regard to process engineering. These regulations can be applied in analogy process steps to the new compounds according to the invention. The person skilled in the art can readily introduce the novel meanings according to the invention for the radical R 2 compared to the European application mentioned, which are customary chemically per se, using numerous standard methods.

    Die Verbindungen der allgemeinen Formel I fallen dabei normalerweise in Form von racemischen Gemischen an, die mittels bekannter Verfahren in die Enantiomeren getrennt werden. Beispielsweise wandelt man mit einem optisch aktiven Spaltungsmittel das Racemat in Diastereomere um, die anschließend durch selektive Kristallisation getrennt und in die entsprechenden optischen Isomeren überführt werden. Als optisch aktive Spaltungsmittel dienen z.B. optisch aktive Basen, wie 1- und d-1-Phenyl-ethylamin, Cinchonidin oder d-Ephedrin, aus denen Salze der Säuren der allgemeinen Formel I, oder optisch aktive Alkohole, wie Borneol oder Menthol, mit denen Ester aus den Säuren der allgemeinen Formel I hergestellt werden. Als besonders geeignet hat sich die Racematspaltung der Säuren mittels Dehydroabiethylamin als Salzbildner herausgestellt.The compounds of general formula I usually fall in the form of racemic mixtures in the enantiomers by known methods be separated. For example, one uses an optically active cleavage agent the racemate into diastereomers, which are then converted by selective crystallization separated and converted into the corresponding optical isomers. Serving as optically active splitting agents e.g. optically active bases, such as 1- and d-1-phenylethylamine, Cinchonidine or d-ephedrine, from which salts of the acids of the general Formula I, or optically active alcohols, such as borneol or menthol, with which esters are prepared from the acids of general formula I. As special The resolution of the racemates by means of dehydroabiethylamine has been suitable exposed as a salt former.

    Die folgenden Beispiele sollen die Erfindung näher erläutern, ohne sie danei einzuschränken.The following examples are intended to illustrate the invention without restricting it.

    Beispiel 1:Example 1:

    Die erfindungsgemäßen Verbindungen der Formel I erniedrigen die Glucosekonzentration im Blut von Ratten, die durch längeres Fasten in einen insulinresistenten Zustand gebracht worden sind. Sie zeigen sich bei dieser Wirkung den aus dem Stand der Technik bekannten Wirkstoffen, z.B. rac-Etomoxir (siehe EP 046 590) überlegen.The compounds of the formula I according to the invention lower the glucose concentration in the blood of rats that have been fasting into an insulin resistant Condition. With this effect they show up from the Active substances known in the art, e.g. rac-etomoxir (see EP 046 590) think.

    In der folgenden Tabelle werden die untersuchten repräsentativen Substanzen zur Kennzeichnung nummeriert: Nummer Name der Verbindung 1 2-(6-(4-Chlorphenoxy)hexyl)oxiran-2-carbonsäureethylester (Vergleichsverbindung) 2 2-(6-(4-Difluormethoxyphenoxy)hexyl)oxiran-2-carbonsäure-ethylester 3 2-(5-(4-Difluormethoxyphenoxy)pentyl)oxiran-2-carbonsäure-ethylester 4 2-(5-(4-Acetylphenoxy)pentyl)oxiran-2-carbonsäureethylester The representative substances examined are numbered in the following table for identification: number Name of the connection 1 2- (6- (4-chlorophenoxy) hexyl) oxirane-2-carboxylic acid ethyl ester (comparative compound) 2 2- (6- (4-Difluormethoxyphenoxy) hexyl) oxirane-2-carboxylic acid ethyl ester 3 2- (5- (4-Difluormethoxyphenoxy) pentyl) oxirane-2-carboxylic acid ethyl ester 4 2- (5- (4-acetylphenoxy) pentyl) oxirane-2-carboxylate

    In der Tabelle 1 sind folgende Befunde dargestellt:

    In Spalte A
    die blutglucosesenkende Wirkung der repräsentativen Substanzen an insulinresistenten Ratten (nach 24 Stunden Fasten) 2 Stunden nach oraler Administration von äquimolaren Dosen (100 umol/kg Körpergewicht),
    in Spalte B
    die triglyceridsenkende Wirkung der repräsentativen Substanzen im Blutplasma von gefütterten, gesunden Ratten nach 16-tägiger oraler Administration äquimolare Dosen (100 umol/kg Körpergewicht) 24 Stunden nach der letzten Substanzadministration,
    in Spalte C
    die cholesterinsenkende Wirkung der repräsentativen Substanzen im Blutplasma von gefütterten, gesunden Ratten nach 16-tägiger oraler Administration von äquimolaren Dosen (100 umol/kg Körpergewicht) 24 Stunden nach der letzten Substanzadministration.
    Angegeben werden prozentuale Änderungen der mit Substanz behandelten Tiere im Vergleich zu mit Placebo behandelten Kontrolltieren, errechnet aus den Mittelwerten von jeweils 10 Einzelwerten. Substanznummer (A) Glucose (%) (B) Triglyceride (%) (C) Cholesterin (%) 1 -18 -50 -15 2 -27 -69 -13 3 -27 -73 -26 4 -7 -41 -8 The following findings are shown in Table 1:
    In column A
    the blood glucose-lowering effect of the representative substances on insulin-resistant rats (after 24 hours of fasting) 2 hours after oral administration of equimolar doses (100 µmol / kg body weight),
    in column B
    the triglyceride-lowering effect of the representative substances in the blood plasma of fed, healthy rats after 16 days of oral administration of equimolar doses (100 μmol / kg of body weight) 24 hours after the last substance administration,
    in column C
    the cholesterol-lowering effect of the representative substances in the blood plasma of fed, healthy rats after 16 days of oral administration of equimolar doses (100 µmol / kg body weight) 24 hours after the last substance administration.
    Percentage changes of the animals treated with substance compared to placebo-treated control animals are given, calculated from the mean values of 10 individual values in each case. substance number (A) glucose (%) (B) triglycerides (%) (C) cholesterol (%) 1 -18 -50 -15 2 -27 -69 -13 3 -27 -73 -26 4 -7 -41 -8th

    Die Überlegenheit der erfindungsgemäßen Verbindungen gegenüber dem Stand der Technik bezüglich der Glucosesenkung im Hungerzustand, gewählt als experimentelles Modell der Insulinresistenz, zeigt sich besonders am Beispiel der Substanzen Nr. 2 und 3 in Tab. 1. Unter Berücksichtigung der triglycerid- und cholesterinsenkenden Wirkung zeichnet sich besonders Substanz Nr. 3 durch eine dem Stand der Technik überlegene Wirkung aus.The superiority of the compounds of the invention over the prior art Technique for lowering glucose in the state of hunger, chosen as experimental The insulin resistance model is particularly evident in the example of substances Nos. 2 and 3 in Tab. 1. Taking into account the triglyceride and cholesterol-lowering Effect No. 3 is particularly characterized by the state of the art Technology superior effect.

    Beispiel 2:Example 2:

    In Tabelle 2 ist der Einfluß der repräsentativen Substanzen auf unerwünschte Nebeneffekte, die in der wissenschaftlichen Literatur beschrieben worden sind (K. Ratheiser, B. Schneeweiss et al.: Metabolism Clin. Exp. 40 (1991) 1185; H.P.O.Wolf in C.J. Bailey & P.R. Flatt, New antidiabetic drugs, Smith-Gordon, London 1990), dargestellt:

    In Spalte A
    der transiente Anstieg der Aktivität des Leberenzyms Glutamat-Pyruvat-Transaminase (GPT) im Blutplasma nach 16-tägiger oraler Administration äquimolarer Dosen der Substanzen an gesunde, gefütterte Ratten 24 Stunden nach der letzten Substanzadministration,
    in Spalte B
    der Anstieg des relativen Herzgewichtes (Herzgewicht / 100 g Körpergewicht) als Zeichen einer Herzhypertrophie nach 16-tägiger oraler Administration äquimolarer Dosen der Substanzen an gesunde, gefütterte Ratten 24 Stunden nach der letzten Substanzadministration,
    in Spalte C
    der sicherheitspharmakologische Index, gebildet aus der prozentualen Senkung der Blutkonzentrationen Glucose + Triglyceride + Cholesterin dividiert durch die prozentualen Erhöhungen GPT-Aktivität + rel. Herzgewicht .
    Substanznummer (A) GPT-Aktivität (%) (B) rel. Herzgew. (%) (C) Sicherheitsindex (%) 1 8 14 3.77 2 5 14 5.74 3 12 11 5.48 4 -9 -2 56 Table 2 shows the influence of the representative substances on undesirable side effects which have been described in the scientific literature (K. Ratheiser, B. Schneeweiss et al .: Metabolism Clin. Exp. 40 (1991) 1185; HPOWolf in CJ Bailey & PR Flatt, New antidiabetic drugs, Smith-Gordon, London 1990), shown:
    In column A
    the transient increase in the activity of the liver enzyme glutamate pyruvate transaminase (GPT) in the blood plasma after 16 days of oral administration of equimolar doses of the substances to healthy, fed rats 24 hours after the last substance administration,
    in column B
    the increase in the relative heart weight (heart weight / 100 g body weight) as a sign of cardiac hypertrophy after 16 days of oral administration of equimolar doses of the substances to healthy, fed rats 24 hours after the last substance administration,
    in column C
    the safety pharmacological index, formed from the percentage reduction in blood concentrations glucose + triglycerides + cholesterol divided by the percentage increases in GPT activity + rel. Heart weight.
    substance number (A) GPT activity (%) (B) rel. Heart custom. (%) (C) Security index (%) 1 8th 14 3.77 2 5 14 5.74 3 12 11 5:48 4 -9 -2 56

    Je höher der Index, desto größer ist die Sicherheit der Substanz zu beurteilen. Unter diesem Aspekt zeichnet sich die Substanz Nr. 4 als dem Stand der Technik besonders überlegen aus. Auch die Substanzen Nr. 2 und 3 sind dem Stand der Technik überlegen.The higher the index, the greater the safety of the substance. Under In this aspect, substance no. 4 stands out as the state of the art superior. Substances Nos. 2 and 3 are also state of the art think.

    Beispiel 3:Example 3: Versuchstiereexperimental animals

    Als Versuchstiere wurden männliche Sprague-Dawley Ratten der SPF-Zuchr Ivanovas (Kisslegg, Deutschland) mit einer Körpermasse von 255 - 400 g verwendet. Die Haltung der Tiere erfolgte konventionell zu je 4 Tieren in Mkrolonkäfigen (22 x 38 cm) in einem temperierten Raum (21 -23 Grad Celcius) mit festem Tag /Nacht-Rhythmus
    (7/19 Uhr) und regulierter rel.Luftfeuchtigkeit von 55 - 60 %. Den Tieren wurde eine Haltungsdiät Altromin 1320 der Fa. Altromin (Lage,Deutschland) und Wasser ad libitum angeboten.     Male Sprague-Dawley rats from SPF-Zuchr Ivanovas (Kisslegg, Germany) with a body mass of 255-400 g were used as test animals. The animals were kept conventionally with 4 animals each in Mkrolon cages (22 x 38 cm) in a temperature-controlled room (21-23 degrees Celsius) with a fixed day / night rhythm
    (7/7 p.m.) and regulated relative humidity of 55 - 60%. The animals were offered an Altromin 1320 husbandry diet from Altromin (Lage, Germany) and water ad libitum.

    Zur Bestimmung der Substanzwirkung auf die Blutglucose wurde zur Erzeugung eines insulinresistenten Zustandes das Futter 24 Stunden vor der Substanzadministration entzogen.To determine the substance effect on blood glucose was used for generation in an insulin-resistant condition, the feed 24 hours before substance administration withdrawn.

    Die Tiere wurden randomisiert in 5 Gruppen zu je 10 Tieren eingeteilt und markiert. Die Substanzen wurden den Tieren in Form einer neutralen, wäßrigen Emulsion (1 Gew.-Teil Substanz + 2 Gew.Teile Cremophor EL - ein Emulgator der Fa. BASF AG, Deutschland - ) mittels einer Magensonde in einem Volumen von 10 ml / kg Körper-gewicht verabreicht.The animals were randomly divided into 5 groups of 10 animals each and marked. The substances were administered to the animals in the form of a neutral, aqueous emulsion (1st Part by weight of substance + 2 parts by weight of Cremophor EL - an emulsifier from BASF AG, Germany -) using a gastric tube in a volume of 10 ml / kg Body weight administered.

    Beispiel 4:Example 4: Gewinnung von Blut und SerumCollection of blood and serum

    Zur Bestimmung der Glucose im Blut wurde den 24 Stunden nüchterenen Tieren 2 Stunden nach Substanz-administration 50 ul Blut mittels einer Galskapillare aus dem retrobulbären Venenplexus entnommen und in eiskalter Perchlorsäure (0,66 mol/l) enteiweißt. Nach Zentrifugation erfolgte die Bestimmung der Glucose im Überstand nach enzymatischen Standardverfahren.To determine the glucose in the blood, the 24-day fasting animals were Hours after substance administration, 50 μl of blood was drawn out using a Gals capillary taken from the retrobulbar venous plexus and in ice-cold perchloric acid (0.66 mol / l) deproteinized. After centrifugation, the glucose was determined in the Supernatant according to standard enzymatic methods.

    Zur Bestimmung der Parameter Triglyceride, Cholesterin und der Aktivität der Glutamat-Pyruvat-Transaminase (GPT) wurde Blutplasma verwendet. Das Blutplasma wurde 15 Minuten nach der venösen Blutentnahme in heparinisierte Eppendorf- Reak-tionsgefäße durch Zentrifugation (2 x 2 Minuten bei 16 000 U/min in einer Eppendorf - Zentrifuge) als erythrocytenfreier Überstand gewonnen.To determine the parameters triglycerides, cholesterol and the activity of Blood plasma was used for glutamate pyruvate transaminase (GPT). The blood plasma 15 minutes after venous blood was drawn into heparinized Eppendorf Reaction vessels by centrifugation (2 x 2 minutes at 16,000 rpm in one Eppendorf centrifuge) obtained as an erythrocyte-free supernatant.

    Beispiel 5:Example 5: Analytische MethodenAnalytical methods

    Glucose:Glucose:
    Enzymatischer Test mit Hexokinase / Glucose-6-phosphatase, Testcombination von Boehringer Mannheim, Deutschland.Enzymatic test with hexokinase / glucose-6-phosphatase, Test combination from Boehringer Mannheim, Germany.
    Triglyceride:triglycerides:
    Enzymatischer Test mit Lipase / Glycerokinase, Testkombination von Boehringer Mannheim, Deutschland. Enzymatic test with lipase / glycerokinase, test combination by Boehringer Mannheim, Germany.
    Cholesterin:Cholesterol:
    Enzymatischer Farbtest (CHOD-PAP-Methode), Testkombination von Boehringer Mannheim, DeutschlandEnzymatic color test (CHOD-PAP method), test combination by Boehringer Mannheim, Germany
    GPT: GPT :
    Kinetischer Enzymtest, Testkombination von Boehringer Mannheim, Deutschland.Kinetic enzyme test, test combination from Boehringer Mannheim, Germany.
    rel. Herzgewicht:rel. Heart Weight:
    Nach Tötung der Tiere durch Dekapitation und Entbluten durch Wägung festgestelltes Gewicht des vom rechten Vorhof befreiten Herzmuskels und Bezug auf 100 g Körpergewicht.After killing the animals by decapitation and bleeding by weighing determined weight of the heart muscle freed from the right atrium and reference to 100 g body weight.

    Claims (6)

    1. Arylalkyl- or aryloxyalkyl-substituted oxiranecarboxylic acids of the general formula I
      Figure 00200001
      in which
      Ar
      denotes a substituted phenyl radical
      Figure 00200002
      a 1- or 2-naphthyl radical which is substituted by an R4 radical, or a heterocyclic radical Het,
      R1
      denotes a hydrogen atom, a halogen atom or a 1-4 C-(lower alkyl) group,
      R2
      denotes one of the groups
      Figure 00200003
      or a fully or predominantly fluorine-substituted 1-3 C-alkoxy group,
      R3
      denotes a hydrogen atom or a 1-4 C-(lower alkyl) group,
      R4
      denotes a hydrogen atom, a 1-4 C-(lower alkyl) group, an optionally fully or predominantly fluorine-substituted 1-3 C-alkoxy group or a halogen atom,
      R5
      denotes a 1-4 C-(lower alkyl) group,
      Y
      denotes the -O- group,
      n
      denotes an integer from 2 to 8, and
      Het
      denotes a heterocyclic ring having 5 members from the group consisting of thiophene, thiazole, isothiazole, pyrrole and particularly preferably pyrazole, which may carry 1-2 identical or different substituents R1,
      where the -(CH2)n- chain may optionally also be interrupted by a -CH(CH3)- or -C(CH3)2- member, and the salts of the carboxylic acids (R3 = H).
    2. Compound of the formula I according to Claim 1, selected from the following group:
      ethyl 2-(6-(4-difluoromethoxyphenoxy)hexyl)oxirane-2-carboxylate
      ethyl 2-(5-(4-difluoromethoxyphenoxy)pentyl)oxirane-2-carboxylate
      ethyl 2-(5-(4-acetylphenoxy)pentyl)oxirane-2-carboxylate.
    3. Medicament of the formula I according to Claim 1 or 2.
    4. Medicament according to Claim 3 for use in the treatment and for the prophylaxis of diseases based on disorders of glucose and/or fat metabolism, such as conditions with pathological glucose tolerance, prediabetes, type 2 diabetes, conditions with insulin resistance, conditions with pathologically increased ketogenesis, hyperlipidaemia, arteriosclerosis and/or coronary heart disease.
    5. Pharmaceutical preparation, characterized in that it comprises one or more compounds of the formula I according to Claim 1 or 2, optionally together with excipients and/or adjuvants.
    6. Use of arylalkyl- or aryloxyalkyl-substituted oxiranecarboxylic acids according to Claim 1 or 2 for the preparation of medicaments for the treatment and prophylaxis of diseases based on glucose and/or fat metabolism disorders, such as conditions with pathological glucose tolerance, prediabetes, type 2 diabetes, conditions with insulin resistance, conditions with pathologically increased ketogenesis, hyperlipidaemia, arteriosclerosis and/or coronary heart disease.
    EP98909391A 1997-02-14 1998-02-05 Oxiran carboxylic acids for the treatment of diabetes Expired - Lifetime EP0966455B1 (en)

    Applications Claiming Priority (3)

    Application Number Priority Date Filing Date Title
    DE19705718 1997-02-14
    DE19705718A DE19705718A1 (en) 1997-02-14 1997-02-14 New oxirane carboxylic acids to treat type 2 diabetes and other insulin resistant conditions
    PCT/EP1998/000611 WO1998035952A1 (en) 1997-02-14 1998-02-05 Oxiran carboxylic acids for the treatment of diabetes

    Publications (2)

    Publication Number Publication Date
    EP0966455A1 EP0966455A1 (en) 1999-12-29
    EP0966455B1 true EP0966455B1 (en) 2004-01-28

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    AT (1) ATE258550T1 (en)
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    CA (1) CA2280960C (en)
    DE (2) DE19705718A1 (en)
    DK (1) DK0966455T3 (en)
    PT (1) PT966455E (en)
    WO (1) WO1998035952A1 (en)

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    US8013014B2 (en) * 2002-07-05 2011-09-06 Georgia Tech Research Corporation Aza-peptide epoxides
    US7056947B2 (en) * 2002-07-05 2006-06-06 Georgia Tech Research Corp. Aza-peptide epoxides
    CA2515368A1 (en) 2003-02-13 2004-08-26 Luciano Rossetti Regulation of food intake and glucose production by modulation of long-chain fatty acyl-coa levels in the hypothalamus
    US7482379B2 (en) * 2004-02-18 2009-01-27 Georgia Tech Research Corporation Propenoyl hydrazides

    Family Cites Families (8)

    * Cited by examiner, † Cited by third party
    Publication number Priority date Publication date Assignee Title
    DE3063144D1 (en) * 1979-09-07 1983-06-16 Byk Gulden Lomberg Chem Fab Substituted oxirane carboxylic acids, process for their preparation, their use and medicines containing them
    US4337267A (en) 1980-08-25 1982-06-29 Byk Gulden Lomberg Chemische Fabrik Gmbh Phenalkoxyalkyl- and phenoxyalkyl-substituted oxiranecarboxylic acids, their use and medicaments containing them
    IL66365A0 (en) * 1981-07-24 1982-11-30 Byk Gulden Lomberg Chem Fab Phenylalkyloxiranecarboxylic acids,a process for their preparation,their use,and medicaments containing them
    EP0231367B1 (en) * 1985-08-02 1991-07-24 Wolf, Horst P.O., Dr. Use of oxirancarboxylic acids for the treatment of hyperlipemia
    US4788306A (en) * 1987-04-03 1988-11-29 American Home Products Corporation Fluorooxirane carboxylates as hypoglycemic agents
    US4788304A (en) * 1987-12-07 1988-11-29 American Home Products Corporation Phospholipase A2 inhibitors
    US5447954A (en) * 1992-05-05 1995-09-05 Smithkline Beecham P.L.C. Phenylderivate as inhibitors of ATP citrate lyase
    KR980009260A (en) * 1996-07-02 1998-04-30 주상섭 Osiranic carboxylic acid derivative and its manufacturing method

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    DK0966455T3 (en) 2004-05-17
    CA2280960C (en) 2007-04-17
    DE19705718A1 (en) 1998-08-20
    WO1998035952A1 (en) 1998-08-20
    EP0966455A1 (en) 1999-12-29
    DE59810675D1 (en) 2004-03-04
    US6670481B2 (en) 2003-12-30
    PT966455E (en) 2004-08-31
    US6479676B1 (en) 2002-11-12
    JP2000509726A (en) 2000-08-02
    CA2280960A1 (en) 1998-08-20
    ATE258550T1 (en) 2004-02-15
    JP3357378B2 (en) 2002-12-16
    AU6394698A (en) 1998-09-08

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